Coronary heart disease continues to be a leading cause of morbidity and mortality in developed countries. It is rapidly assuming similar trends in developing countries also. The heart operates similar to a pulsatile pump, in that blood enters the arteries intermittently with each heart beat, causing pressure pulses in the arterial system. In a healthy circulatory system, the pressure at the height of a pulse (systolic pressure is approximately 120 mm Hg and the pressure at the lowest point of the pulse (diastolic pressure) is approximately 80 mm Hg. The difference between these two pressures, 40 mm Hg, is termed the pulse pressure (Guyton and Hall, TEXTBOOK OF MEDICAL PHYSIOLOGY 221 (6th ed., W. B. Saunders Company, 1956) (1981)). Stroke volume output of the heart and compliance of the arterial system are the two most important factors in pulse pressure.
Atherosclerosis, which is the principal cause of death in Western countries, decreases arterial compliance by depositing calcified plaques on arterial walls, thereby reducing the elasticity of arterial walls. When this occurs, systolic pressure increases greatly, while diastolic pressure, the pressure that causes blood to be transferred from the arteries to the veins, is decreased greatly. Thus, blood becomes backed-up in the system, due to the inability of blood to flow through the arteries efficiently, as well as, the inability of blood to flow back to the heart. One key process of artherosclerosis is the accumulation of lipids resulting in distribution of atheromatous plaque. As plaque accumulates in the inner artery wall, the restricted artery is weakened, bulging with cholesterol and toxic deposits. Eventually, the plaque blocks the arteries and interrupts blood flow to the organs they supply. Thus, hyperlipidemia (elevated levels of lipids), and specifically, hypercholesterolemia (elevated levels of cholesterol) are major risk factors for atherosclerosis.
It is known that there are three forms of cholesterol: very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Arterial wall cholesterol, and therefore atherosclerotic plaque, consists almost exclusively of LDL. Overwhelming evidence shows that LDL cholesterol becomes harmful only in its oxidized form known as oxysterol. HDL on the other hand, has been found to be inversely associated with coronary artery disease. It has been determined that for every 1 percent increase in the HDL cholesterol level, the risk of having a coronary event is decreased 3 percent. There are two generally accepted approaches to preventing CVD. The first is to lower LDL cholesterol levels and/or increase HDL cholesterol levels and the other is to reduce levels of oxidized cholesterol.
Several studies have demonstrated that lowering LDL cholesterol levels reduces death from heart disease. The Scandinavian Simvastatin Survival Study followed 4,444 men and women with a history of angina or heart attack over 5.4 years (344 LANCET 1383-389 (1994)). The study showed that simvastatin, a cholesterol lowering drug, was effective at lowering LDL and thus decreasing deaths and the need for bypass and angioplasty surgery. The Cholesterol and Recurrent Events Trial demonstrated that pravastatin, another cholesterol lowering drug, was effective at lowering LDL cholesterol by 28%, heart attacks by 25%, and strokes by 28%. The study involved 4,158 men and women with a recent history of heart attack (Sacks et al., 335 N. ENGL. J. MED. 1001-1009 (1996)).
A host of LDL cholesterol lowering drugs is currently on the market. The most widely used lipid-lowering drugs include simvastatin, pravastatin, lovastatin, fluvastatin, atorvastatin, and cerivastatin, which make up the group of HMG-CoA reductase inhibitors known as statins. The statins inhibit one of the enzymes responsible for manufacturing VLDL in the liver (HMG-CoA reductase). In response to a lower level of VLDL, the liver removes LDL from the bloodstream to compensate for the loss of VLDL, thereby reducing LDL cholesterol levels in the blood. Statins have also been found to increase HDL levels in some patients. Although effective, the statins are associated with several side effects including reversible liver enzyme elevations, gastrointestinal upset, headache, dizziness, mild skin rashes, muscle pain and muscle inflammation at high dosages. Moreover, serious liver toxicity is possible. Side effects notwithstanding, recent coronary angiography trials have revealed that if LDL cholesterol can be lowered below 100 mg/dl using cholesterol lowering drugs, atherosclerosis. progression is arrested in only 50% to 60% of patients. Alternative cholesterol lowering drugs include: (1) fibrates, gemfibrozil and clofibrate, which activate the enzyme lipoprotein lipase, resulting in a lowering of triglycerides and possibly VLDL; and (2) bile acid sequestrants, better known as resins, cholestyramine and colestipol, which binds and removes bile acids in the intestines. The liver requires cholesterol to make more bile acids and therefore removes LDL from the blood for this function. Fibrates and resins have not found widespread use because the former is associated with hepatitis and a two-fold increased risk of gallstones and the later is associated with gastrointestinal discomfort and an increase in triglycerides, another CHD risk factor. An analysis of several studies even showed a slight increase in overall deaths due to the use of fibrates.
An additional approach to preventing CVD is the reduction of blood triglyceride level. Most fats eaten in food or converted from carbohydrates exist in the form of triglycerides. Hypertriglyceridemia, i.e., elevated blood triglyceride level, is a well known risk factor for coronary heart disease. The fibrates described above are the most effective drug for lowering triglyceride level but is only moderately effective for lowering LDL. Combination drug therapy has thus become more popular in recent years.
It has now been generally accepted that LDL cholesterol becomes harmful only in its oxidized form. Native LDL consists of phospholipids, triglycerides, cholesterol, both free and as an ester, fatty acids (50% of which is polyunsaturated), proteins and lipophilic antioxidants that protect the polyunsaturated fatty acids (PUFA) in cholesterol against free radical attack and oxidation. The first step in the oxidation of cholesterol is the production of free radicals, which are generally induced by oxidative stress. These radicals act to deplete lipids of their natural antioxidants, such as vitamin E and carotinoids, and are also highly reactive against proteins, DNA, PUFA and lipids. Once the natural antioxidants are depleted, the free radicals move to oxidize unprotected LDL. The oxidized cholesterol molecule is recognized by scavenger receptors and internalized by macrophages in the form of lipid loaden foam cells, the first step in the formation of atherosclerotic plaque. Oxidative stress may occur when formation of reactive oxygen species increases, scavenging of reactive oxygen species or repair of oxidatively damaged macromolecules decreases, or both. Thus, factors such as exposure to environmental pollutants and pesticides can instigate the generation of oxysterols internally.
Nutritional aspects of atherosclerosis include the role of antioxidants in the diet such as beta-carotene, selenium, vitamin E, and vitamin C. Fats and cholesterol are very susceptible to free-radical damage and form lipid peroxides as well as oxidized cholesterol when exposed to free radicals. These products of free-radical damage impair artery walls and accelerate the progression of atherosclerosis.
Vitamin E has been studied in depth for its effects on cardiovascular disease. For example, studies have shown that supplementation with just 30 IU to 100 IU of vitamin E results in patients having a 41% lower risk of heart disease. Another study showed that supplementation with 100 IU of vitamin E results in reduced progression of coronary artery disease. Despite these earlier promising results, more recent findings suggest that vitamin E has no effect on foam cell production, although supplementation with vitamin E does indeed increase the levels of vitamin E in cells such as macrophages. The same study concluded that there is a direct correlation-between foam cell production and depletion of cellular vitamin E, though this does not correlate with the amount of cell lysis by oxidized LDL.
More recent efforts towards anti-atherogenic drugs have been directed at compounds with properties. Amlodipine, a new-calcium antagonist, was determined to normalize elevated levels of oxidized LDL cholesterol without reducing elevated total plasma cholesterol levels. Initial results indicate that atherosclerosis progression was suppressed in monkeys who had been fed an atherogenic diet. Monatepil, an alpha 1-adrenoceptor-blocking drug with antilipid peroxidation activity was also found to reduce plasma lipid levels.
Polyphenols have been associated with beneficial effects in the prevention of atherosclerosis. Many plant phenols and flavonoids contain important dietary antioxidants. It has been speculated that compounds found in red wine or in the Mediterranean diet could explain the “French paradox”. This would explain why there is a lower mortality rate due to cardiovascular disease in France and Mediterranean countries, as compared to the other developed countries such as the United States, though the French diet is high in polysaturated fats. Substituted phenols and thiophenols have been documented as antioxidant chemicals for inhibiting the peroxidation of LDL cholesterol as well.
South America offers a wide diversity of plants and unique seasonal crops mainly due to the presence of natural areas such as the Andean mountains or the Amazon rainforest. Several scientific reports have pointed out the therapeutic potential of certain food plants from Andean mountains such as “maca” (Lepidium meyenii) and “yacon” (Smallantus sonchifolius) that have been linked to multi-pharmacological properties. Cyclanthera pedata Schrad is of South American origin, where it is known by the common name of “achojcha”, “achocha”, “caygua”, “caihua”, “achuqcha” (quechua name). It is thought to be native to the Andean region or “Sierra”, and was cultivated by the Incas who used its fruits as food. The fruit is a berry (10-20 cm length) with irregular surface, soft spines and longitudinal grooves. Its color varies from dark green to white. The mesocarp (edible part) is thin and succulent. The endocarp is white and fluffy. Its seeds are roughly quadrangular and rough black. Actually, the “achojcha” fruits are largely used in South America to make salad or soup for their medicinal properties popularly attributed, such as anti-inflammatory, hypoglycemic and hypocholesterolemic. It thus represents an example of a plant used for medicinal purposes, and can appropriately be considered within the above-described context of food plant with health-giving effects. For this reason, C. pedata has a commercial interest in the functional food market. The nations involved in promoting the diffusion of this species are Peru, Ecuador (in particular the southern part), Bolivia, Colombia, Venezuela and north of Argentina. Fruits and seeds are rich in cucurbitacins, which are important as chemotaxonomic markers. A number of studies have highlighted the presence of saponins in fruits and seeds and O and C-glycosides of chrysin and apigenin in fruits. It was recently described inhibitory activity of angiotensin I-converting enzyme (ACE).
Cyclanthera pedata (also known as Caigua, “cucumber filling”, “Suñez”, Achogcha, Peruvian Maxixe and many other names as further shown below) is a slender tropical vine that is indigenous to South America. It grows up to 40 feet in length with long tendrils for climbing. The leaves are 4-5 inches wide and divided into several lobes. It produces a pale green, semi-flattened fruit resembling a cucumber that is 4-6 inches long and 2-3 inches wide. Unlike a cucumber, the inside of the ripe fruit is hollow (much like a bell-pepper), with several black seeds attached to a placenta. In South America the fruits are eaten much like bell peppers—either raw or cooked (after the seeds are removed). They are also prepared as stuffed peppers; stuffed with meat, fish or cheese and then baked—earning its name “stuffing cucumber.” Caigua is currently cultivated as a food in the Caribbean, Central and South America. It has been introduced into Florida where it is called “wild cucumber” and is considered a weed pest in lawns and gardens.
Domesticated in the Andes and traditionally distributed from Colombia to Bolivia, the caigua is now grown in many parts of Central America and also in parts of the Eastern Hemisphere tropics. For example, caiguas are very popular in northeastern India, Nepal and Bhutan. The Moche culture had a fascination with agriculture and displayed this in their art. Caiguas were often depicted in their ceramics. Typically, the immature fruits are eaten cooked, raw in salads, and pickled. The caigua has a subtle flavour similar to other edible cucurbit fruits. The fruit has a large cavity in which the seeds develop, and this can be filled with other foods to make caigua dishes. This may have inspired the local Andean name pepino de rellenar (“stuffing cucumber”). The young shoots and leaves may also be eaten as greens.
There are about 30 species of Cyclanthera that are native to warm-temperate and tropical America. Caigua can stand more cold than many others and it can be found growing prolifically in mountainous valleys in South America up to 3,000 m in elevation. The plant is known in Peru by its Spanish name caigua or caihua. Its indigenous Quechua name is achocha or achoccha. Achocha is a plant of the tropics, where it can be found at elevations up to 3,000 meters. It can also be cultivated in the subtropics and in areas of the temperate zone that have a long, warm growing season of 4 months or more. Requires a very warm, sunny and sheltered position in a rich well-drained soil. The plant is considered to be a weed pest in Florida. The first harvest of fruit can take place about 3 months after planting, and can then continue for several months.
In herbal medicine systems in Peru, a tea from the fruit seeds is used for controlling high blood pressure. The seeds are also dried and crushed and taken in 1 gram doses for intestinal parasites. The seeds and/or the fruits are also recommended for gastrointestinal disorders. The leaves of caigua are considered hypoglycemic and prepared in a decoction for diabetes. The fruits are boiled in milk and gargled for tonsillitis. The fruit juice is also recommended for high cholesterol, hypertension, tonsillitis, arteriosclerosis, circulatory problems, diabetes and as a diuretic. The fruit and/or the leaves are boiled in olive oil and used externally as a topical anti-inflammatory and analgesic. The roots are used to clean the teeth.
It is also known that caigua seeds contain 28-30 amino acids as well as a group of trypsin inhibitors. The leaves of the plant were recently reported to contain two new malonyl derivatives. The fruits are known to contain flavonoid glycosides including four novel ones never reported before that have shown an antioxidant effect in laboratory research. In addition, the fruits have yielded nine triterpenoid saponins, among them six new natural compounds never seen before. The seeds have been reported with six new cucurbitacin glycosides
Plant chemicals reported in caigua fruit include phenols, peptin, galacturonic acid, picrin, lipoproteins, flavonoids, glycosides, mucilage, alkaloids, lipids, tannins, terpenes, resins, carbohydrates, sterols, scoparin, vitamins, vitexin, and minerals.
Research conducted in Peru has reported that caigua can lower cholesterol levels in humans. A double-blind placebo study with 60 patients over one year reported that 82% of the patients lowered their total cholesterol by an average of 18.3% by reducing LDL by 23% and raising HDL-levels by 42%. Patients were given either a placebo, 2 or 4 or 6 300 mg capsules daily of dehydrated fruit juice. Another study with 29 patients reported similar results in 10 days with total cholesterol dropping by 21.1% (LDL decreased by 63.55% and triglycerides by 36.37%). These subjects were given 100 cc daily of fruit juice (the equivalent of about 6 fresh fruits). Another study with 17 patients reported an average drop in cholesterol of 21.51% after 21 days taking two (300 mg dehydrated fruit juice) capsules daily (LDL decreased by 22.57% and triglycerides by 16.33%). In a 12-week study with postmenopausal women taking 6 (300 mg) capsules of caigua dehydrated fruit juice, they reported women lowered LDL cholesterol by 33% and increased HDL by 33%. There were no drug interactions, contraindications or side effects reported in any of the studies.
Caigua products have been gaining in popularity and availability in the U.S. natural products market over the last several years. Most are marketing these supplements as a cholesterol management aid, for hypertension, and blood-sugar regulation. Most of the available products in the United States are tablets or capsules of the dried or freeze-dried fruit juice.